US5981291A - Estrogen marker system - Google Patents

Estrogen marker system Download PDF

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US5981291A
US5981291A US08/855,590 US85559097A US5981291A US 5981291 A US5981291 A US 5981291A US 85559097 A US85559097 A US 85559097A US 5981291 A US5981291 A US 5981291A
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body fluid
estrogen
free
molar
anthocyanin pigment
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Dorothee Goldman
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Oratel Diagnostics LLC
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • G01N33/743—Steroid hormones
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/689—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to pregnancy or the gonads
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/805—Test papers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/806—Fertility tests
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/97—Test strip or test slide
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S436/00—Chemistry: analytical and immunological testing
    • Y10S436/815—Test for named compound or class of compounds
    • Y10S436/817—Steroids or hormones
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S436/00—Chemistry: analytical and immunological testing
    • Y10S436/906—Fertility tests

Definitions

  • the present invention is directed to a method for determining the capacity of a body fluid to hold "free” estrogens using a unique marker system that is sensitive to changes in the solubility of estrogens in body fluids. More specifically the present invention is directed to a simple, quick and non-invasive and easy to use system which can monitor changes in the body's capacity to hold "free" estrogens in order to permit for screening and early identification of physiological changes and conditions that are estrogen dependant.
  • Estrogens include a group steroid hormones essential for normal development and for the healthy functioning of the reproductive system. Three of these estrogens include 17 ⁇ estradiol, estriol, and estrone. Evaluation of "free" estrogen levels can have diagnostic importance in screening for abnormal patterns of changes in estrogen solubility levels such as is observed in the growths of certain estrogen dependent tumors, occurrence of cystic ovaries, and the development of possible endometriosis in the reproductive organs of females. In some female mammals changes in concentration of "free" estrogens are known to occur at the time of implantation and before the onset of parturition. It is also known that "free" estrogen levels vary at different times of the life span of a mammal.
  • estriol which is produced by the adrenal glands of the fetus.
  • estriol one estrogen form called estriol.
  • Prior to delivery estrogen levels increase significantly in serum and saliva of different species of pregnant mammals. After delivery, estrogen levels fall rapidly in the mother and babies have low levels of "free" estrogens.
  • estrogen levels increase significantly in girls before they reach puberty. As women age, their ability to produce estrogen decreases after the onset of menopause and "free" estrogen levels reach very low levels between 70 and 80 years. Estrogen levels also fall when ovaries are removed from all animal species.
  • the body has a system to regulate the total amount of "free" estrogens at any given time.
  • An ovulating woman can absorb at least 9 picograms of free estrogen in her saliva.
  • a woman who is about to deliver a baby will be able to absorb at least 200 picograms of "free” estrogen in her saliva.
  • An old woman who is menopausal will have only 1-2 picograms of "free” estrogen in her saliva.
  • the body is able to recognize when the capacity to have "free” estrogens is reached. Excess estrogens become bound to other components in the body fluids thus preventing these excess estrogens from acting as hormones.
  • a system that can evaluate whether or not the body has reached its capacity to hold "free” estrogens can have many useful applications and can have considerable clinical value and importance as a tool for screening for various conditions affected by changes in "free” estrogen levels. This is especially true in females. It can be used to evaluate when a body fluid is increasing its capacity to hold "free” estrogens such as is observed in serum and saliva prior to parturition. It can also be used by menopausal women to monitor how the body is absorbing estrogen therapy. It can further evaluate imbalances in "free” estrogen levels such as observed in ovarian cysts. It can track estrogen level changes in the normal development of an individual such as in the last stages of fetal development, the onset of puberty, menopause, and other estrogen dependent events.
  • anthocyanins pigments as a fertility evaluation medium is known and is described in U.S. Pat. No. 4,358,288 to Goldman.
  • This patent describes evaluating fertility in females by contacting a mucin-containing body fluid such as saliva with a fertility evaluation medium comprising an anthocyanin pigment and a substrate which facilitates generation of a color response in this pigment in the presence of a vaginal fluid or substance similar to those found in vaginal fluids.
  • This patent does not, however, suggest that observed color changes in anthocyanin pigments under certain specific conditions can be correlated with the capacity of body fluids to hold free, unbound estrogens and can be used to screen for estrogen dependent physiological changes in the body that do not include fertility evaluation.
  • a given body fluid such as saliva, serum, or interstitial fluid
  • Yet another object of the invention is to provide a simple yet effective method to quantitatively determine what is the additional capacity for "free" estrogens in a body fluid such as saliva, serum, or interstitial fluids.
  • a method to identify changes in the capacity to hold "free" estrogens in the body fluids of animals which comprises providing a marker that is sensitive to estrogen solubility, which is an anthocyanin pigment on a substrate that facilitates color change or other optical response in the pigment when contacted with an estrogen containing body fluid such as saliva, serum or interstitial fluid in the presence of dilute solutions of calcium salts.
  • anthocyanin pigment that, upon contact with a body fluid, give a color response or other measurable optical response that correlates with the capacity of the body fluid to hold "free” estrogens.
  • This system involves a color response that occurs when saliva or some other body fluid (such as serum or interstitial fluid having pH values between 5.8 and 7.3) are contacted with a defined concentration of certain anthocyanin pigments in the presence of a dilute solution of calcium salts. If maximum levels for "free" estrogen already exist in the body, the anthocyanin pigments will show a strong blue response and any added concentrations of "free” estrogens to this body fluid will cause the blue color to increase in intensity.
  • saliva or some other body fluid such as serum or interstitial fluid having pH values between 5.8 and 7.3
  • body fluid samples that need small amounts of the added estrogen to achieve this color change are close to their limit.
  • Body fluid samples that can absorb large amounts of an added estrogen have larger limits in their capacity to hold "free" estrogens.
  • the anthocyanin system for evaluating the capacity to hold "free" estrogens in a body fluid has a composition comprising an anthocyanin pigment that is mounted onto a substrate which provides for a color response when this treated substrate comes in contact with body fluids that are at pH values between pH 5.8 and 7.2 and are also in contact with a dilute solution of calcium salt.
  • kits to evaluate the free estrogen capacity of any given body fluid which includes a substrate such as transparent sheets or strips of glass, acetate, or polyethylene or acrylic or containers or cuvettes made of similar transparent materials that are coated or sprayed with defined concentrations of an anthocyanin pigment, a second component such as a wick made of cotton or cellulose or a molecular sieve that can filter components greater than 20,000 Daltons out of the body fluid, a third component including dilute aqueous solutions of calcium salts preferably in concentrations between 10 -2 to 10 - molar, and a fourth component comprising a color comparison chart for comparing color responses produced in the test to colors provided by the chart that reflect defined levels of maximum capacity for "free" estrogens.
  • a substrate such as transparent sheets or strips of glass, acetate, or polyethylene or acrylic or containers or cuvettes made of similar transparent materials that are coated or sprayed with defined concentrations of an anthocyanin pigment
  • a second component such as a wick made of cotton or cellulose or a
  • the "free" estrogen capacity evaluation kit may optionally include standardized units of a certain estrogen concentration which can be used for a quantitative assay to evaluate the additional capacity of body fluid to hold "free” estrogens, and a final component comprising written instructions in assisting the user on how to use the kit and interpret the results in order to screen for physiological changes that are estrogen dependent.
  • the present invention provides many advantages over current technology to evaluate changes in unbound "free" estrogen levels in animals. First, it is non-invasive and requires small amounts of sample to register a color change. Second, it is simple and easy to prepare. Third, it is quick and easy to read. Fourth, it is accurate and can identify changes in estrogen capacity within +/-2 picograms of a certain type of estrogen per milliliter.
  • the anthocyanin estrogen solubility marker method of the present invention offers many benefits to current estrogen evaluation processes. First this method can be done at home, on a farm, or in a zoo using body fluids that can be obtained in a non-invasive manner. Additionally, small samples of body fluid (between 10 microliters and 150 microliters) are sufficient to give accurate results. Furthermore, this method can be done quickly. Saliva can be exposed to the estrogen solubility marker system in less than 30 seconds and immediately a clearly defined color response gives feedback about the body's capacity to hold "free" estrogens. A simple, easy to read, estrogen solubility marker system offers new opportunities to make early screening for many physiological conditions that are estrogen dependant.
  • an estrogen marker system that is sensitive to changes in the solubility of estrogens has practical value in anticipating parturition in livestock and in humans. Frequently, there is a great deal of guess work about whether a pregnant female is in labor or not. Sometimes parturition is induced when it is too early and sometimes it is postponed because not enough information is available to indicate the appropriate time.
  • a simple test that measures one parameter of events that are known to be part of the physiological process involved in parturition can improve the guess work and have diagnostic value as well as help individuals to be better prepared for the actual birthing process.
  • clinics and research institutions may have need for a practical non-invasive device that allows for quick measurement of maximum levels of free estrogens as a routine diagnostic tool to monitor certain aspects of fetal development or to evaluate certain physiological conditions that are estrogen dependant.
  • a measurement which relies on body fluids such as saliva avoids painful blood samples and cuts down on potential infections and other problems that can develop from measuring estrogen solubility levels from blood samples.
  • FIG. 1 is a graph illustrating the measurement of Rf values of saliva exposed to anthocyanin pigments extracted from red roses
  • FIG. 2 is a graph similar to that of FIG. 1 for saliva samples taken from a woman one year after her ovaries had been removed;
  • FIG. 3 is a graph comparing color readings on anthocyanins pigments from a woman six weeks after her ovaries had been removed;
  • FIG. 4 is a graph illustrating color values of saliva from a woman with no ovaries after having been on estrogen therapy
  • FIG. 5 is a graph illustrating absorbance values for saliva from a woman
  • FIG. 6 is a graph illustrating optical density versus estradiol
  • FIG. 7 is a graph illustrating the optical density values for distilled water over time.
  • FIG. 8 is a graph comparing optical density values for saliva incubated with estradiol.
  • the anthocyanins used in the estrogen solubility marker system of the present invention have the following general formula which is based on an equilibrium ratio of two anhydrobase forms of the anthocyanin pigment as they exist at pH vales between 5.5 to 7.5.
  • the pigment structure varies between ##STR1## wherein R 1 is selected from the group consisting of hydrogen, and C 1 -C 4 alkoxy; R 2 is selected from a group consisting of hydrogen, hydroxy, and C 1 -C 4 alkoxy, and R 3 is glycoside selected from a group of glucosides and R 5 is either a hydrogen or a glycoside selected from the group consisting of glucosides and X is a cation.
  • the concentration of the pigment must fall within the following ranges. 5 ⁇ 10 -5 molar to 1 ⁇ 10 -3 molar. This range is very important because molar concentrations above 1 ⁇ 10 -3 do not give clear definable results and molar concentrations below 1 ⁇ 10 -5 do not give accurate optical density measurements. At pH levels between 5.8 and 7.2 a molar concentration between 8.0 ⁇ 10 -5 and 2.0 ⁇ 10 -4 gives best results.
  • the tested medium must be between the pH ranges of 5.0 and 7.5 preferably between 5.8 and 7.2.
  • the following form of the anthocyanin pigment is favored in the equilibrium ratio when the "free" estrogen capacity is at its maximum levels. ##STR2##
  • optical absorbance values are best read between 560 nm and 580 nm.
  • the absorbance values would range between 0.1 and 1.0 for concentrations of anthocyanin pigments between 8 ⁇ 10 -5 molar and 2 ⁇ 10 -4 molar and the visible color would be blue or purple depending on the type of anthocyanin pigment used and the actual molar concentration of the pigment.
  • the absorbance values read between 550 nm and 580 nm.
  • the range of absorbance readings would be below 0.2 and rapidly approach values less than 0.09 and the visible color would range between purple and pale purple or clear.
  • anthocyanin pigments that have 3,5 glucosides.
  • Anthocyanin pigments that have a glycoside on the 7 position do not give intelligible results.
  • the preferred anthocyanin for estrogen solubility determination has been documented to be malividin 3,5 diglucoside. Pelagorian 3,5 diglucoside gives good results. Petuidin 3,5 diglucoside also give definable results. Preparations from cyanidin 3,5 diglucoside do not give as well defined results because of the greater instability of cyanidin 3,5 diglucoside in the conditions necessary for these procedures.
  • the body fluid that is to be tested should come in contact with the cotton wick or cellulose first.
  • the body fluid travels up the wick about 1 mm to 10 mm and the wicked wet body fluid comes in contact with the dried pigment that has been laid onto a non-cellulose transparent surface such as acetate or glass.
  • the body fluid should be kept at temperature between 36 and 90 Fahrenheit. This range is important because it has been observed that heating the body fluid over 100 Fahrenheit destroys the ability to evaluate changes.
  • Anthocyanin pigments are prepared in certain molar concentrations in methanol sprayed or painted onto the surface of the plastic or glass to cover a certain surface area in a given period of time.
  • Small plastic beads are coated with anthocyanin pigments and these are placed either behind a piece of cellulose or inside a membrane that separates particles greater than 20,000 Daltons outside and allows for particles less than 20,000 to enter inside the membrane where there is contact with the anthocyanin pigments.
  • the method to determine if the body fluid contains maximum levels of soluble "free" estrogens involves taking a sample of defined volume of the body fluid and exposing this sample to a given concentration of anthocyanin pigment.
  • Method 1 A defined volume of body fluid between 1 microliter and 10 microliters is put onto a piece of chromatographic paper that is in contact with a bead or surface that has 1 microliter to 10 microliters of a given concentration of anthocyanin pigment and this treated chromatographic paper is put into a chromatographic bath and exposed fluid is allowed to migrate up the chromatography paper for a given amount of time.
  • the body fluid comes in contact with the anthocyanin pigment and the combination of the pigment and the body fluid continues migrating with the chromatographic bath fluid up the chromatographic paper at different rates.
  • the exposed chromatographic paper is removed and allowed to dry at room temperature.
  • this chromatographic paper is sprayed with a dilute ammonia solution and measurements are made for the distance that the chromatography solution travels. This value is called the Rf value. If the Rf value is greater than 0.4 then the body fluid is approaching its maximum capacity to absorb more "free" estrogens. If the Rf value is from 0.1 to 0.36 then the body fluid is far from it maximum capacity to hold "free" estrogens, as best shown in FIGS. 1 through 4.
  • Method 2 About 1 microliter to 20 microliters of body fluid sample is exposed to a cotton wick or filter paper that absorbs the body fluid like a wick and this body fluid travels along the wick to a plate that has previously been sprayed or dipped with a given concentration of anthocyanin pigment and then dried at room temperature. When the wet body fluid comes in contact with the dried pigment, a color response is observed that is either dark blue, purple, or clear. If dark blue is observed, the maximum level to absorb estrogen has been reached. If a clear color is observed or a pale pink color is observed, then the body fluid is able to increase its capacity to hold more estrogen.
  • Method 3 One to 3 ml. of body fluid sample is filtered to remove large particles of preferably greater than 20,000 Daltons and 150 microliters suprernatent or filtered sample is put into a container with a liquid preparation of the anthocyanin pigment at a given molar concentration and a color evaluation can be made. If a dark blue color occurs, the sample is near its maximum capacity to hold free estrogen. If little or no color response is observed, the sample has the capacity to absorb more free estrogen. In like manner, these filtered body fluid samples can also be evaluated with a spectrophotometric machine that evaluates optical density at a given wavelength.
  • a molar concentration of an anthocyanin pigment at 2 ⁇ 10 -4 moles/ml that is read at a wavelength of 560 nm, that gives an absorbance value of less than 0.09 means that the capacity to absorb more estrogen is not at its maximal level.
  • An absorbance value for the same molar concentration and read at the same wavelength that is between 1.0 and 2.0 means that the body fluid has maximum level of estrogen capacity and added amounts above a certain concentration of estrogen will result in increased absorbance values as best shown in FIG. 5.
  • An absorbance value between 0.1 and 1.0 means that capacity is somewhere between the maximum level and the minimum level 0.1 being closer to the minimum level and 0.9 being closer to the maximum level).
  • Method 4 In certain body fluids such as plasma or the saliva of certain animals such as ungulates, it has been observed that it is necessary to add dilute amounts of calcium salts in order to observe these color changes.
  • This method involves mixing the body fluid with the anthocyanin pigment as described in any of the procedures presented above as in steps 1, 2 or 3 and then after the body fluid has been exposed to the anthocyanin pigment according to the prescribed procedure, a defined unit of dilute concentration of 1 ⁇ 10 -2 molar Ca Cl 2 or any Ca salt solution is added to this combination. If the resulting color of this procedure is blue or has a high absorbance value as measured in a spectrophotometer, then the body fluid is close to or at its maximum level of "free" estrogen capacity. If the resulting color response is pink than the capacity to absorb more "free" estrogen is not at its maximum level.
  • a system to determine what is the additional capacity of the saliva to absorb more "free” estrogen can be done by adding given concentrations of "free” estrogens such as a prepared concentration of 17 ⁇ estradiol and counting how many units of this estradiol concentration are needed to cause the color response to change or the absorbance value to decrease. When the color response turn back to blue or the absorbance value goes up, then the maximum capacity has been reached and the number of units of estradiol need to achieve this state become additional capacity that the body fluid has to absorb more estrogen.
  • FIG. 6 shows how optical density values change for saliva from a 90 year old man who does not have gonads.
  • the initial optical density value for the given concentration of anthocyanin added to saliva sample was 0.303 and the color response was purple. This value indicates that the saliva capacity to hold free estrogen was not at its maximum and not at its minimum.
  • Adding increments of 6 pg/ml of free estradiol up to 27 pg/ml showed a constant decreased-optical density value of about 0.06.
  • the optical density began to increase and continued to increase up to 135 pg/ml.
  • Another application of this invention has been to anticipate the onset of labor in pregnant women. About two weeks prior to delivery in full term pregnancies, there is a color shift in the saliva test as used on the cellulose wick exposed anthocyanins extracted from rose pigments. (During most of pregnancy, the color response is blue or purple blue). Two weeks prior to delivery the color response shifts to pink or no blue. This color response remains until the day labor begins when it shifts to a clear, pale blue response about 6 hours prior to delivery as observed in eight spontaneous deliveries of full term pregnancies. This patter of color changes has also been observed in induced deliveries which were observed to shift from blue to purple within 20 minutes to 2 hours after induction was initiated and then proceed to delivery within 4 to 12 hours after the purple color response was observed.

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Cited By (5)

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US20100267003A1 (en) * 2006-04-03 2010-10-21 Dorothee Goldman Methods and kit for endometriosis screening
WO2012024095A2 (en) 2010-08-20 2012-02-23 Oratel Diagnostics, Llc Estrous cycle monitoring by color response
DE102012002929A1 (de) * 2012-02-14 2013-08-14 Jürgen Lewald Minimalinvasives Verfahren für die Diagnose und die Therapieverlaufskontrolle der Endometriose
US8841130B2 (en) 2011-07-11 2014-09-23 Oratel Diagnostics, Llc Methods and kit for endometriosis diagnosis
WO2022194862A1 (en) 2021-03-16 2022-09-22 Breedsense As Method for predicting the likelihood of pregnancy in female mammals which experience an estrous cycle

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CA2215958C (en) * 1995-03-23 2009-09-15 Dorothee Goldman Method and apparatus for evaluating estrogen dependent physiological conditions
EP2821071A1 (en) 2013-07-04 2015-01-07 Institut d'Investigació Biomèdica de Bellvitge (IDIBELL) Compounds for breast cancer treatment

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JPH11506535A (ja) 1999-06-08
AU5526296A (en) 1996-10-08

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